PROJECT SUMMARY/ABSTRACT Millions of young children are exposed to general anesthesia each year. Exposure of young animals to anesthesia can cause neurodegenerative changes with adverse effects on learning and behavior. The concern generated by these observations is highlighted by the recent FDA issuance of a Drug Safety Communication warning that general anesthesia and sedation drugs used in children < 3 years of age who were undergoing prolonged or repeated exposures ?may affect the development of children?s brains.? In prior work, we studied the association between anesthesia exposure prior to age 3 and neurodevelopmental phenotype, as assessed by a detailed neuropsychological assessment of 997 children sampled from a propensity-matched, population-based birth cohort (children born in Olmsted County, MN from 1994-2007). Children exposed to multiple anesthetics had consistent deficits in cognitive processing speed and fine motor skills, without significant deficits in other domains including general intelligence, memory, and executive function. These deficits were associated with behavioral problems and learning difficulties as reported by parents, including an increased frequency of attention-deficit/hyperactivity disorder (ADHD) and learning disabilities. Conditions such as ADHD are associated with structural and functional brain abnormalities in children as revealed by MRI scans We performed preliminary imaging studies in the children tested in the prior studies and found that children multiply-exposed to anesthesia also demonstrate consistent neuroanatomical changes. The central hypothesis of this proposal is that exposure to anesthesia prior to age 3 is associated with specific structural and functional changes in the brain as assessed by MRI. The Specific Aim of this proposal is to determine if the neurodevelopmental abnormalities of these children are associated with specific changes in brain MRIs. To accomplish this aim, children will be recruited from among those Olmsted County children already phenotyped in our prior work, based on anesthesia exposure history (100 each of unexposed, singly-, and multiply-exposed children). Their brains will be imaged in a novel 3T MRI scanner, with a protocol including 3-D T1-weighted and T2-weighted anatomic sequences, resting-state functional MRI, and diffusion tensor imaging. We will determine the relationship between MRI findings, anesthesia exposure, and neurocognitive findings to evaluate the hypothesis that brain imaging measurements mediate the association of anesthesia exposure with neurocognitive outcomes. The expected product of this research could be the first biomarker for anesthesia-associated neural injury in children. Consistent imaging changes (as suggested by our preliminary data), despite the considerable variation between children regarding factors such as type of procedure and socioeconomic status, could provide important insights into potential mechanisms responsible for injury.